This Project focuses on the autoimmune hypothesis recently proposed as a possible etiology for Tourette's syndrome (TS) and related disorders. The hypothesis is that antibodies against group A beta-hemolytic streptococci antigen(s) cross-react with neuronal proteins and compromise neuronal function. We will test this hypothesis through analyses of neuroimaging, immunological, molecular biological, and genetic data. We will determine whether significant volumetric increases exist in the basal ganglia of these individuals who have had recent streptococcal infections. This will be determined by MRIs taken at the time bloods are obtained. We are fortunate to already be in possession of a large number (N=377) of biological samples, including sera, DNA, MRIs, and extensive clinical assessments from work completed through the previous funding cycle of the program project. We will now determine whether autoantibodies are present in patients' sera using three independent techniques: immunofluorescence, ELISAs, and Western blots. We will identify and characterize proteins that are consistently recognized by patients' sera. Patients with autoimmune disorders often share specific HLA alleles within the histocompatability complex. We propose to now test whether a similar sharing of alleles exists for these subjects. The DR and DQ alleles for all patients will be determined. We will develop an experimental model by transferring affinity-purified antibodies into rat pups. Injections will be made both intraventricularly and into the peritoneal cavity. These experiments will first determine whether the antibodies are able to cross into the brain and whether they label specific structures within the CNS. We will also inject antigens recognized by patients' sera which we have purified biochemically. Finally, antibodies generated against these purified antigens will also be injected. The finding of biological markers within homogeneous subgroups will advance our understanding of the pathophysiology of TS and related disorders and lead to improved treatments.